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(01/21/2014) Autism Risk Gene Controls Normal Brain Wiring, Report McLean Hospital Researchers

Integrative Neurobiology Laboratory

Christopher W. Cowan, PhD, Director

The Integrative Neurobiology Laboratory (INL), under the direction of Dr. Christopher Cowan, seeks to identify novel genes, proteins and molecular mechanisms that control proper brain wiring during development, and to understand the role of these basic processes in the young and adult brain under chronic pathological conditions (e.g drug addiction, depression, anxiety disorders, autism spectrum disorders, intellectual disability, etc). 

Integrative Neurobiology Laboratory Staff

The Integrative Neurobiology Laboratory Staff
(click to enlarge)

The Cowan lab utilizes cutting-edge experimental techniques and broad interdisciplinary, translational research approaches to interrogate the regulation of brain development and function, and to better elucidate the underlying deficits in brain function that contribute to neuropsychiatric and neurodevelopmental disorders.

Drug Addiction:
Drug addiction is a complex human disease characterized by intense drug craving and persistent drug taking despite profound negative consequences to the individual. Understanding the neuronal, molecular and brain circuit plasticity that controls addiction-associated behavioral maladaptations will facilitate the development of therapeutics that can treat or prevent this debilitating condition. Studies in humans suggest that nearly half of the factors predisposing an individual to addiction are genetic, yet the genes, proteins and molecules that contribute to addiction-related behaviors are only beginning to be discovered.  Our lab combines in vivo approaches (behavior testing, genetically-modified animals, viral-mediated gene delivery, and neuronal imaging) with a number of complementary in vitro approaches (cultured neurons, slice pharmacology and electrophysiology) to interrogate genetic, cell signaling, gene expression and synaptic mechanisms regulated by drugs of abuse. We continue to expand our repertoire of experimental approaches, which now include rodent intravenous drug self-administration, to gain a more integrated and holistic understanding of the genes and cell processes associated with the development and maintenance of addiction-related behaviors.  We have many ongoing studies in adult mice and rats exploring the role and regulation of several genes implicated in cocaine-induced behavioral and synaptic plasticity, including: Fmr1 (Fragile X Mental Retardation Protein gene), MEF2, HDAC5, HDAC4, Npas4, mGluR5, and Arc.

Autism:
Autism Spectrum Disorders (ASDs) are likely caused by abnormalities in proper brain wiring and function during early development.  Normal brain wiring requires the proper guidance of neuron fibers to appropriate brain regions and the subsequent establishment and remodeling of functional synapse, key points of communication between neurons.  Currently, the INL is exploring the role of two gene families recently linked to autism. The goal of our research is to understand how these genes contribute to normal brain development, and to understand how disruption of these genes contributes to the risk of developing ASD symptoms.

1.  Thalamic and Cortical Axon Guidance: Recent work from Dr. Matt State (Yale) identified rare, highly disruptive mutations in autism patients in the Simons Simplex Collection, including EPHB2 gene, revealing it as a new candidate risk gene for autism.  The Cowan lab has been studying the role of the EphB Receptor genes in early brain development in mice.  Eph Receptors are a large class of cell-surface proteins that regulate numerous brain development processes including:  (1) guidance of nerve fibers to their appropriate destinations in the brain, (2) the formation and remodeling of chemical synapses, and (3) changes in synapse strength induced by experience.  The Cowan lab recently identified an essential role for EphB1 and EphB2 Receptors in thalamocortical and corticothalamic axon guidance during early brain development. Consistent with current views on autism and cortical under-connectivity, we seek to explore the possibility that dysfunction of EPHB2, and similar genes, and possible brain wiring defects contribute to autism phenotypes in a subset of patients.  Supported studies by the Simons Foundation will seek to build a crucial link between the genetics and neurobiology of EPHB2, a promising new autism candidate gene.

2. Synapse Elimination in Brain Development:
The development of brain synapses in humans occurs during late prenatal periods and throughout the first few years of a child’s life. Proper synaptic formation and brain wiring requires a complex interaction between brain activity, driven in large part by sensory experience, and neuronal gene expression. Many of the genes whose mutations are linked to autism play a role in synapse formation or pruning during brain development. Some individuals with autism show an excess of excitatory synapses, consistent with a deficit in synaptic pruning. Synaptic pruning is a normal developmental process that results in the elimination of synapses to refine the neural circuitry in the brain.  Our lab, in an ongoing collaboration with Dr. Kim Huber at UT Southwestern Medical School (Dallas, TX), studies several genes that are required for proper synaptic pruning in the normal brain and that have links to autism. We have found that the MEF2 transcription factors, in response to synaptic activity, trigger the elimination of excitatory synapses, and this process requires the RNA-binding protein, FMRP (Fragile X Mental Retardation Protein). The gene that produces FMRP, FMR1, is the causal gene in Fragile X Syndrome -- a neurodevelopmental disorder characterized in part by autism symptoms in affected individuals. Recently, we discovered that protocadherin genes are important for MEF2/FMRP-dependent synapse elimination, and active studies are seeking to understand the critical roles these genes play in synapse pruning and neural circuit plasticity.

Our lab has several ongoing studies exploring behavioral and brain connectivity phenotypes in mutant mice, including cutting-edge social behaviors, repetitive behaviors, and analysis of ultrasonic vocalizations, a key mode of social communication in mice. These studies are currently funded by the Simons Foundation SFARI grants.

Depression and Anxiety:
Disorders of mood, including major depressive disorder (MDD) and anxiety disorders, are pervasive illnesses for which few effective treatment options exist. A more thorough understanding of the molecular and cellular mechanisms underlying these conditions is needed to develop more efficacious treatments. Accumulating evidence points to disrupted structural and functional plasticity of limbic brain regions following periods of stress, a common precipitating factor for MDD (and relapse to drug seeking in addiction).  The lab has several ongoing projects exploring the regulation and role of several synapse-regulating genes in the brain reward regions, the nucleus accumbens, and the prefrontal cortex, in the development and maintenance of anxiety and depression-related behaviors and functional and structural changes in synapses in these mesolimbic reward circuits in the rodent brain.

In addition, we are using mouse genetic models and cutting-edge molecular approaches to explore the possible common molecular, cellular and genetic links in the brain reward circuitry that might contribute to strong prevalence (comorbidity) of both addiction and mood disorders in patients.

Staff

01.2014